Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Comparing transplant outcomes in ALL patients after myeloablative conditioning in mismatch-related or unrelated donor settings.

The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes.

Total Body Irradiation and Fludarabine with Post-Transplant Cyclophosphamide for Mismatched Related or Unrelated Donor HCT.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment for most patients with hematological malignancies. A well-matched donor (related or unrelated) remains as the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we described outcomes of patients who underwent mismatched donor (related or unrelated) HCT with radiation-based MAC regimen in combination with FLU, and PTCy as higher intensity GVHD prophylaxis. We analyzed outcomes based on donor type. METHODS: We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT [related/haploidentical vs unrelated (MMUD)] with fractionated-total body irradiation (FTBI) plus fludarabine and post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis at City of Hope from 2015 to 2021. Diagnoses included ALL (46.5%), AML (36.1%) and MDS (6.5%). The median age at HCT was 38 years and 126 (81.3%) patients were from ethnic minorities. HCT-CI was ≥3 in 36.1% and 29% had a disease-risk-index (DRI) of high/very high. Donor type was haplo (67.1%) or MMUD (32.9%). RESULTS: At 2-years post-HCT, disease-free survival (DFS) and overall survival (OS) for all subjects were 75.4% and 80.6%, respectively. Donor type did not impact OS [HR=0.72, (95% CI: 0.35,1.49), p=0.37] and DFS [HR=0.78, (95% CI: 0.41,1.48), p=0.44] but younger donors resulted in less grade III-IV acute GVHD (aGVHD, [HR=6.60, (95% CI: 1.80,24.19), p=0.004] and less moderate or severe chronic GVHD [HR=3.53, (95% CI: 1.70,7.34), p<0.001] with a trend toward better survival (p=0.099). MMUD led to significantly faster neutrophil (median 15 vs 16 days, p=0.014) and platelet recovery (median 18 vs 24 days, p=0.029); however, there was no difference in GVHD outcomes between these groups. Non-relapse mortality [HR=0.86, (95% CI: 0.34,2.20), p=0.76] and relapse risk [HR=0.78, 95%CI: (0.33,1.85), p=0.57] were comparable between the two groups. Patient age <40-years and low-intermediate DRI showed a DFS benefit (p=0.004 and 0.029, respectively). High or very High DRI was the only predictor of increased relapse [HR=2.89, 95%CI: (1.32, 6.34), p=0.008]. CONCLUSION: In conclusion, FLU/FTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of relationship with patient, provided promising results, and improved access to HCT for patients without a matched donor especially patients from ethnic minorities and mixed race.

Autoimmune Hemolytic Anemia in a Patient With COVID-19 Pneumonia: A Case Report on a Rare Presentation.

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) pneumonia can have a range of clinical presentations ranging from being asymptomatic to having severe acute respiratory syndrome (SARS). Autoimmune hemolytic anemia (AIHA) is a very rare presentation of COVID-19. We present the case of a 67-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) who presented to the emergency department (ED) with shortness of breath and was found to be COVID-19-positive. His laboratory results demonstrated autoimmune hemolytic anemia with decreased hemoglobin (Hgb), elevated lactate dehydrogenase (LDH), decreased haptoglobin, peripheral smear showing spherocytes, and a positive direct antiglobulin (Coombs) test. The patient was started on glucocorticoids, but his hemoglobin continued to worsen. The dose of glucocorticoids was increased significantly, and his hemoglobin started improving with the resolution of hemolysis. Autoimmune hemolytic anemia is usually treated with glucocorticoids, but escalating glucocorticoid doses increases the risk of side effects. This case report highlights the importance of further research needed to establish guidelines for AIHA in the context of COVID-19 pneumonia.